dendrimer to deliver si-RNA molecules to target cells. The branches of dendrimers can attach or trap other molecules. “You can also modify them chemically to attach specific cell targeting molecules,” adds Professor Catapano. Synthesis of the dendrimer-based
nanoparticles remains a key challenge and requires high-level expertise in chemistry. The dendrimers can be produced in a range of sizes that affect their solubility and dispersion in the body and adding targeting molecules can also alter the dendrimer’s properties. Another aspect that requires careful balancing is the capability to assemble the molecules and release the si- RNA at the right time. The release process itself is something of a ‘black box’ thought to be triggered by changes in the intracellular pH. The field is still very new and full of unknowns. “It’s exciting but it’s also very complex and difficult,” he laughs. Professor Catapano has many years of
experience in experimental oncology. The work in the current project grew from previous studies into transcription and
Molecular dynamics simulation of a dendrimer si-RNA complex
“You can have molecules that can block three or four genes, for example, important for a certain type of cancer”
epigenetic factors that are thought to be largely responsible for transforming normal cells into cancer cells. “In the process of these studies we found that to target factors like this, rather than using small molecules like chemotherapeutic drugs, we could use something
like si-RNA,” he explains.
“Because you can make a very specific target gene of interest knock it down and block it.” They also studied what regulates gene
activity and found that there are molecules of RNA called non-coding RNA that do not produce proteins but have regulatory functions inside cells. In fact only a small fraction of RNA molecules in the genome are protein-coding. “This is a relatively new field but we know that some of these regulatory RNA molecules work as a switch to turn genes on and off,” says Professor Catapano. Their anticancer treatments will use si-RNA directed to these regulatory
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non-coding RNA to block the activity of oncogenes so that they do not express in cancer cells. Most
existing chemotherapeutic drugs
block activity of enzymes like protein kinases and little has been done to block other types of activity.
treatments using si-RNA potentially have the advantage. “Small interfering RNA could be a way to target any gene that you think is important,” explains Professor Catapano. One could also
think of
combining ‘cocktails’ of different si-RNA for different targets. “You can have
This is where
molecules that can block three or four genes, for example, important for a certain type of cancer.” Theoretically there should also be fewer
side effects. Small RNA molecules are naturally present
in the body and so are
unlikely to have toxic effects unless overdosing occurs. However as the research is still at such an early stage, this aspect also remains uncertain. The project draws on a range of disciplines
including medical oncology, molecular biology and chemistry. The Consortium researchers also use computational tools,
31
Dendrimer-facilitated uptake of siRNA in cancer cells
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